Project Summary Colorectal cancer (CRC) remains the second leading cause of cancer deaths among Americans underscoring the need for more effective screening practices. Colonoscopy as primary screening has been accompanied by a modest but steady decline in CRC incidence through identification and removal of precursor lesions, the adenomatous polyp. Indeed, there has been a 32% decline between years 2000-2013 in CRC incidence in patients over age 50 (thus eligible for screening). Strikingly, during this same time period, the incidence rate for those under 50 has increased by 22%. Thus, new and effective screening strategies are urgently needed to address the rising burden of CRC (?50 years) which is expected to increase over the next decade with the rising young population. The objective of the R33 Moonshot Project is to develop a highly advanced screening approach to identify the subset of young patients who actually harbor advanced adenomas and could benefit from colonoscopy via a test that is sensitive to advanced adenomas, low-cost, and that can be carried out in a primary care setting. To this end, we have developed a new technology, partial wave spectroscopic (PWS) microscopy or nanocytology. Nanocytology performed on colonocytes swabbed from the rectal mucosa is able to identify nanoscale alterations in higher order chromatin structure, which are highly accurate markers of the presence of advanced adenomas that might be located anywhere in the colon. The goal for the proposed project is to finalize the PWS technology, turn it into a practical, accurate, and low-cost test that is viable for young population screening, and conduct a pre-definitive clinical trial. We aim to achieve sensitivity and specificity over 90%. Upon the completion of this moonshot project, nanocytology will be ready for a definitive clinical trial, which can lead to CLIA approval and launch in clinical practice as a laboratory-developed test (LDT).